单核巨噬细胞在触发脓毒症和形成免疫抑制中起着至关重要的作用，但调控机制未明。我们发现G蛋白偶联家族（GPCR）分子GPR116在脓毒症患者外周血单个核细胞高表达，且与其功能呈负相关。敲减小鼠巨噬细胞GPR116后发现，TLR诱导产生的炎症因子和转录因子NF-κB和MAPK均显著增强，提示GPR116可能负向调控TLR信号通路。机制探讨发现，常规GPCR下游通路未参与其中，而我们用免疫沉淀技术发现一个195KD的蛋白分子诱导性地与GPR116结合，疑似其靶分子，提示GPR116可能以一种新的机制参与TLR信号的负向调控。我们假设：炎症诱导GPR116表达上调与相应靶分子相结合，从而负向调控TLR激活。目前，GPR116与脓毒症及其对TLR信号通路的调控研究均未见报导。本项目将从临床、细胞及转基因动物水平，探讨GPR116在脓毒症中的作用和机制，为脓毒症的治疗提供新思路。

Monocyte/macrophage play a key role in innate immune response as well as immune tolerance during sepsis, but its underlying mechanism remains unknown. Our preliminary experiments found that GPR116, a G protein-coupled receptor (GPCR) family molecule, is overexpressed in peripheral blood mononuclear cells in patients with sepsis, and its mRNA expression is negatively correlated with HLA-DR, a known marker of monocyte function and immunosuppression. We further found that knockdown of GPR116 expression in mouse peritoneal macrophages significantly increased the TLR induced expression of inflammatory factors and the transcription factors NF-κB and MAPK, suggesting that GPR116 may negatively regulate TLR signaling pathway. Mechanically, intervention of GPCR downstream signaling pathway cannot reverse the negative effect of GPR116, indicating that other potential pathways or molecules may be involved in the regulation of TLR signaling by a GPR116. Using immunoprecipitation technology, we find a 195 kD protein molecule binds to GPR116 and seems to be the possible target molecule. We hypothesize that sepsis induces the upregulation of GPR116, and the elevated GPR116 may combine its target molecule to negatively regulating TLR activation through an unknown mechanism before. At present, there is no relative literature reporting the role of GPR116 and its underlying mechanism in sepsis. We will perform the experiments at the molecular level, knockout mouse as well as septic patients to explore the role and its underlying mechanism of GPR116, aiming at finding potential target to sepsis therapy and clarifying the regulation of TLR signaling pathway.